This is a dosage escalation study to estimate the optimum immunization dose of ras peptide mixed with the immunologic adjuvant Detox. Groups of 3 to 6 patients receive the ras peptide/Detox vaccine monthly for 3 months. Patients with stable or responding disease or with a specific immunologic response may receive 3 additional monthly vaccinations.

Condition	Treatment or Intervention	Phase
Neoplasm	Drug: Detox  Drug: RAS Val  Drug: RAS Cys  Drug: RAS Asp  Drug: RAS Peptides	Phase I

Further Study Details: 

Expected Total Enrollment:  33

Cancers in humans are commonly associated with mutations in dominant and recessive oncogenes. These genes produce mutated proteins that are unique to cancer cells. Ras proto-oncogenes are the best characterized mutated genes in human cancers. They encode a highly conserved family of 21 Kd proteins. With a single amino acid mutation, the ras protein can potentiate transforming capabilities both in mouse and human cells. Such point mutated ras have been found in a broad spectrum of human carcinomas notably at codons 12, 13, and 61. Codon 12 mutations form more than 90% of all ras mutations in human cancers. These proteins get degraded in the cells and present themselves as small peptides through the major histocompatibility complex (MHC) molecules on the surface of the cells, this would render these peptides potentially immunogenic through exposure to T lymphocytes.

Animal data have shown that subcutaneous immunization of mice with short synthetic peptides (Ras 5-17) corresponding to different mutations at codon 12 induces specific immune response for some of these mutations.

We propose to test whether point mutated ras peptide can be targeted via vaccination of cancer patients with peptides reflecting those mutants. Patients with cancers that potentially express mutated ras, e.g. colon, pancreas, lung, breast will be screened for the mutated ras gene. Those that have any of 3 specific mutations on codon 12 (Gly to Cys, Gly to Asp, or Gly to Val) will be vaccinated.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Histologic diagnosis of solid tumors potentially expressing mutant ras, including colon, lung, pancreas, breast and prostate.
Tumor tissue availability for determination of ras mutation (paraffin block, or fresh tissue).
ras mutation should be a specific point mutation in codons 12 which include:
Gly to Cys, Gly to Asp, or Gly to Val.
It is preferable to have tumor tissue available for preparation of a tumor cell line, and tumor or lymph node tissue for expansion of tumor infiltrating lymphocytes (TIL) for in-vitro laboratory studies. If fresh tissue is not available, the patient may be requested to undergo a surgical biopsy procedure if the medical status of the patient permits the procedure and minimal patient risk is undertaken. Surgical procedures to be performed are those that can be done under local anesthesia or are otherwise indicated for the standard care of the patient. Patient's consent to such a procedure is not a requirement for protocol entry.
The patient should not have received chemotherapy, radiation therapy, immunotherapy or steroids for at least 4 weeks prior to starting vaccination. And the patient should have recovered from all acute toxicities of previous treatment.
The patient should have metastatic disease for which no further chemotherapy or radiation options which are known to increase survival are available.
On the highest tolerable dose level additional patients will be entered if they have:
Adenocarcinoma of the lung stage II or III after surgery or radiation therapy;
SCLC, limited or extensive disease in CR;
Colorectal Ca Duke C who received appropriate adjuvant chemotherapy;
Fully resected pancreatic or fully resected recurrent colorectal carcinoma.
Patients should be 18 years of age or older.
ECOG performance status of 1 or 0.
Ability to give informed consent.
While measurable disease is preferable, it is not a necessity.
Expected survival more than 3 months.
EXCLUSION CRITERIA:
Any condition that does not fit with Inclusion Criteria.
HIV or Hepatitis B or C infection.
Pregnant women or nursing mothers are ineligible. Women with reproductive potential must have negative pregnancy test. Men and women of reproductive age should use adequate contraception.
Any of the following:
WBC less than 3000/mm (3), Lymphocytes less than 600/mm (3), Platelets less than 100K/mm(3);
Creatinine greater than 2.0 mg/dl;
Serum Bilirubin greater than 2.0 mg/dl, SGOT, or SGPT greater than 4X normal.
History of second malignancy other than curatively treated carcinoma in-situ of cervix or basal cell carcinoma of the skin.
History of CNS metastases.
Patients with active ischemic heart disease (i.e. Class III or VI cardiac disease-New York Heart Association), a recent history of myocardial infarction (within the last 6 months), history of arrhythmia or other clinical symptoms suggesting cardiac or pulmonary insufficiency.
Unresponsiveness to skin test antigens.
Patients with autoimmune disease e.g. SLE, MS, ankylosing spondylitis, etc.
Patient with active infections requiring antibiotics.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States

Study ID Numbers:  940096; 94-C-0096
Record last reviewed:  March 1, 2004
Last Updated:  November 25, 2004
Record first received:  November 3, 1999
ClinicalTrials.gov Identifier:  NCT00001380
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08